This is a renewal application for a Research Scientist Award to permit me to continue my research program with its associated training ofjunior investigators, and to coordinate a large multi-lab research endeavor. Research Program: My group is interested in the pre- and post-synaptic biochemical events associated with adaptation to altered neuronal activity, as well as the functional significance of this neuroplasticity. The work focuses on systems that utilize catecholamines. The work can be divided into three interrelated programs: the biological bases of degeneration and compensation in an animal model of parkinsonism; the consequences of chronic stress on transmitter synthesis and release; and regulation of dopaminergic activity in subcortical regions by cortical input. In this application, I focus on the first of these programs, which has long been the central theme of our research and the focus of my previous applications providing a Research Scientist Award. I emphasize five specific aims designed to determine (l) the extent to which function is preserved after damage to the dopaminergic input to neostriatum, (2) the generality of our model for compensations after partial lesions, looking at other conditions of hypoinnervation including aging, (3) the neurobiological bases for the discrepancies between terminal loss and functional deficits, (4) the neurotoxic consequences of increased dopaminergic activity, and (5) the extent to which tyrosine hydroxylase can be transferred into non-dopaminergic cells to effectively restore dopaminergic activity after extensive neurodegeneration. I believe these studies will provide basic information on the neurobiology of neuronal interactions as well as insights into aspects of several neurological and psychiatric disorders. Research Administration: My lab is composed of about a dozen individuals, including pre- and post-doctoral trainees, senior research associates, and staff. The work is coordinated through weekly "working group" meetings, biweekly lab-wide meeting, and meetings of the administrative and research staff. I also direct two inter-lab research projects involving eight other faculty members and members of their groups. Mentoring: A considerable amount of time is devoted to mentoring members of the lab group. This occurs through regular group meetings as well as individual meetings. Much of the day-to-day supervision of the graduate students occurs through the more senior members of the group. Training: I direct an NIMH-funded training program in basic neuroscience. As part of this effort I run a series of monthly, day-long workshops in areas of professional development and ethics, and participate in a summer training program at the Marine Biological Lab (Woods Hole, MA) for minority students in neuroscience.